Background: The rhizome of Atractylodes lancea (AL) is usually used for the treatment of various diseases such as spleen deficiency syndrome (SDS). Both bran-processed and crude AL is included in Chinese Pharmacopoeia. The different efficacies of bran-processed and crude AL on SDS are largely unknown, and the mechanisms of AL effects have not been fully elucidated. Objective: The objective of the study was to compare the effects of bran-processed and crude AL and then assess the mechanisms of treating SDS. Materials and Methods: The model of SDS in rats was established using excessive exertion, combined with an irregular diet and intragastric administration of the extract of Sennae Folium, and different doses of bran-processed and crude AL were gavaged. The serum was analyzed by an enzyme-linked immunosorbent assay (ELISA), and small intestinal tissues were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Results: The injury of SDS was alleviated by the treatment of bran-processed and crude AL. Compared to model group, the indexes of trypsin (TRY), amylase (AMS), vasoactive intestinal peptide (VIP), somatostatin (SS), gastrin (GAS), substance P (SP), Na+-K+-ATPase, and succinic dehydrogenase in serum of each administration group were increased by ELISA, and the mRNA expressions of VIP, SS, GAS, and SP in small intestinal tissues were increased by RT-PCR. Furthermore, in a dose-dependent manner, the bran-processed and crude AL increased the levels of TRY, AMS, VIP, and GAS and the mRNA expression levels of VIP. Compared with the crude AL, the bran-processed AL was more effective in treating SDS. Conclusion: Through the mechanisms of treating SDS by AL, both bran-processed and crude AL has alleviated the symptoms of SDS.